Description of the methodological approach

  1. We searched for all controlled and uncontrolled studies examining TAAR1 agonists. In this first iteration of the review, we analyzed usable data from all randomized controlled studies comparing any TAAR1 agonist to placebo or current antipsychotics in people with psychosis, other mental health conditions, or healthy volunteers.

  2. We examined efficacy outcomes, including overall symptoms of psychosis (primary) and symptom domains, dropouts due to any reason, and adverse events. Safety outcomes included death, serious adverse events, and specific adverse events. We also sought mechanistic outcomes, specifically neurobiological measures of dopaminergic, glutamatergic, and serotonergic signaling. We examined these outcomes at three time points: immediately after a single dose up to 2 weeks of treatment, 3-13 weeks of treatment (preferably at 6 weeks), and longer-term outcomes.

  3. In terms of efficacy outcomes, we pooled the data for each specific subgroup, considering that differences can be expected among different diagnoses (e.g., schizophrenia and Parkinson’s disease psychosis) and patient subgroups (e.g., patients with an acute episode of schizophrenia or with predominant negative symptoms). In terms of other outcomes, we combined data from all subgroups but also presented data separately for each subgroup.

  4. Summary of data extraction: For continuous outcomes, we preferred change over endpoint scores and data from appropriate models or imputations considering missing outcome data. For dichotomous outcomes, we again preferred data from all participants, but in case of participants with missing outcome data, we assumed that they did not experience the event; an assumption usually used in meta-analysis in schizophrenia (e.g., Huhn et al. 2023). In terms of crossover studies, we preferred data from appropriate models considering period or carry-over effects. If not available, we assumed a correlation (i.e., 0.2 for adverse events) to correct the variance of the estimates according to Elbourne et al. 2002. If an outcome was measured multiple times after a single dose of the drug, we calculated the area under the curve according to the linear trapezoid rule (Chiou et al. 1978) and divided by the time of assessment to remove the time component.

  5. Risk of bias was assessed using the RoB2 tool for parallel and crossover studies. When only one domain had some concerns, we assigned an overall low risk of bias. Otherwise, we used the worst judgment across domains.

  6. The effect sizes were as follows: 1) standardized mean differences (SMD) for efficacy outcomes, given that various scales have been used in the literature to allow comparability of the findings with other studies of antipsychotic drugs; 2) mean differences (MD) for laboratory measures, i.e., weight (kg), QTc interval (msec), and prolactin levels (ng/ml); 3) odds ratios (OR) for dichotomous outcomes, which were also converted to absolute risks using a control event rate (see 7. for meta-analysis). 95% confidence intervals (95% CI) are presented, but 95% prediction intervals are not presented due to the small number of studies. Other effect sizes were not used in the first iteration of the review, e.g., those used in meta-analysis of variance due to the paucity of data.

  7. Meta-analysis was conducted primarily using a random-effects model with inverse variance and REML estimator of tau-squared. Due to the small number of studies (<5) in all analyses, we corrected the confidence intervals using the Hartung-Knapp method, and we also presented the findings from fixed-effects models using the Mantel-Haenszel method throughout. Meta-analysis of proportions was conducted to pool the control groups to estimate the control event rate using logit transformation of the proportions and inverse variance method. Moreover, continuity corrections of 0.5 were applied in case of 0 events in one of the groups.

  8. Sensitivity analysis of the primary outcome included using fixed-effect methods (post-hoc due to the small number of studies), restricting the analysis to studies with an overall low risk of bias, and excluding studies with imputed values.

  9. Subgroup analyses and meta-regressions were not conducted due to the paucity of data. However, we explored potential dose-effects for the primary outcome by plotting the effect sizes for different fixed doses of TAAR1 agonists compared to placebo (while correcting for the use of common comparators).

  10. Summary of evidence tables were constructed for all outcomes, including a summary of the association, biases due to study limitations, biases due to reporting bias, biases due to indirectness, and other biases. We adapted the GRADE approach. We used the ROB-ME approach for evaluating biases in missing evidence for the primary outcomes and considered the percentage of missing studies and participants for secondary outcomes. Indirectness was considered especially relevant for non-efficacy outcomes, where we pooled data across diagnoses and subgroups, and considered the percentage of studies and participants with schizophrenia, the main group for which this evidence would be applicable.

Please see the manuscript and the protocol for more details.

Results

We present below the results, including the PRISMA flow diagram, table of included studies, risk of bias assessment, and forest plots, to facilitate a better understanding of the summary of evidence tables and the manuscript. Please refer to the detailed description of the findings in the latter part of the manuscript for more information.

Flow of study selection

Figure 1 PRISMA 2020 flow diagram

Table of included studies

Name Title ID Sponsor Design Population Intervention Sample size Objectives Start date Completion date Completion year Status Available data
DA801002 (in Galluppi 2021) Population pharmacokinetic analysis of ulotaront in subjects with schizophrenia DA801002 Sunovion/Sumitomo SB-RCT single ascending dose (phase I) Men >18 years Ulotaront (25mg to 50mg); Placebo 16 Pharmacokinetics NA NA 2021 completed None
Fowler (2015) A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure NA Hoffmann-La Roche DB-RCT; single ascending dose (phase I) Men 18-45 years RO5263397 (1mg to 125mg); Placebo 49 Tolerability, pharmacokinetics NA NA 2015 completed None
Hopkins (2021) Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans SEP361-103 Sunovion/Sumitomo DB-RCT two-period crossover; single dose (phase I) Men 18-35 years Cohort 1: Ulotaront 10mg; Placebo; Cohort 2: Ulotaront 50mg; Placebo 24 Sleep parameters, pharmacokinetics NA NA 2021 completed Dropouts, side-effects
Isaacson (2023) Ulotaront, a Trace Amine-Associated Receptor 1/Serotonin 5-HT1A Agonist, in Patients With Parkinson Disease Psychosis: A Pilot Study. SEP361-203, NCT02969369 Sunovion/Sumitomo DB-RCT; 6 weeks (with open label extension) (phase 2) Men/women ≥55 years with Parkinson’s disease psychosis (acute) Ulotaront 20-75mg/d; Placebo 39 Efficacy (acute), safety 21.11.16 05.07.23 2023 completed Efficacy, dropouts, side-effects
JapicCTI-194581 (2019) A Phase I Single-Ascending Dose and Multiple-Ascending Dose Study of RO6889450 in Healthy Japanese Male JapicCTI-194581 Hoffmann-La Roche DB-RCT; single and multiple ascending dose (phase I) Men 20-45 years Ralmitaront; Placebo 64 Tolerability, pharmacokinetics 27.01.19 23.10.19 2019 completed None
Koblan (2016) A phase 1 open label safety and tolerability study of SEP-363856, a novel NON-D2 mechanism of action molecule, in patients with schizophrenia SEP361-106, NCT01994473 Sunovion/Sumitomo SB-RCT; multiple ascending dose for 1 week (including open label extension) (phase 1) Men/women 18-55 years with schizophrenia (stable, DSM-IV-TR) Ulotaront (10mg/d to 100mg/d); Placebo 48 Tolerability, pharmacokinetics 41334 41974 2014 completed None
Koblan (2020) A Non–D2-Receptor-Binding Drug for the Treatment of Schizophrenia SEP361-201, NCT02969382, EUCTR2016-001555-41 Sunovion/Sumitomo DB-RCT; 4 weeks (with open label extension) (phase 2) Men/women 18-40 years with schizophrenia (acute, DSM-5) Ulotaront (50-75mg/d); Placebo 245 Efficacy (acute), tolerability 05.12.16 31.07.18 2018 completed Efficacy, dropouts, side-effects
NCT01940159 (2013) A Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Male and Female Subjects With Schizophrenia SEP361-105, NCT01940159 Sunovion/Sumitomo SB-RCT; single ascending dose (phase 1) Men/women 18-50 years with schizophrenia (stable, DSM-IV-TR) Ulotaront (50mg to 150mg); Placebo 48 Tolerability, pharmacokinetics 41334 41730 2014 completed None
NCT02699372 (2016) The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of RO6889450 in Healthy Volunteers BP30134, NCT02699372 Hoffmann-La Roche DB-RCT; single and multiple ascending dose up to 2 weeks (phase I) Men/women 18-45 years Ralmitaront (5 mg to 450mg); Placebo 164 Tolerability, pharmacokinetics 21.03.16 14.04.17 2017 completed None
NCT03669640 (2018) A Study to Assess the Effects of RO6889450 (Ralmitaront) in Participants With Schizophrenia or Schizoaffective Disorder and Negative Symptoms BP40283, NCT03669640, EUCTR2020-004752-16, JPRN-jRCT2031200287 Hoffmann-La Roche DB-RCT; 12 weeks (phase II) Men/women 18-55 years with schizophrenia or schizoaffective (predominant negative symptoms, DSM-5) Part A: Ralmitaront; placebo (monotherapy); Part B: Ralmitaront low or high dose; placebo (add-on to current antipsychotics) 128 Efficacy (negative symptoms), tolerability 04.12.18 08.05.23 2023 completed None
NCT04072354 (2019) A Clinical Trial to Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia SEP361-301, NCT04072354, EUCTR2019-000470-36 Sunovion/Sumitomo DB-RCT; 6 weeks (phase 3) Men/women 13-17 and 18-65 years with schizophrenia (acute, DSM-5) Ulotaront 50mg/d; Ulotaront 75mg/d; Placebo 463 Efficacy (acute), tolerability 11.09.19 08.06.23 2023 completed Efficacy, dropouts
NCT04092686 (2019) A Clinical Trial That Will Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia SEP361-302, NCT04092686, EUCTR2019-000697-37 Sunovion/Sumitomo DB-RCT; 6 weeks (phase 3) Men/women 18-65 years with schizophrenia (acute, DSM-5) Ulotaront 75mg/d; Ulotaront 100mg/d; Placebo 462 Efficacy (acute), tolerability 30.09.19 08.09.23 2023 completed Efficacy, dropouts
NCT04115319 (2019) A Study of the Long-term Safety and Tolerability of an Investigational Drug in People With Schizophrenia. SEP361-304, NCT04115319 , EUCTR2019-002259-40 Sunovion/Sumitomo DB-RCT; 52 weeks (phase 3) Men/women 18-65 years with schizophrenia (stable, DSM-5) Ulotaront 50-100mg/d; Quetiapine XR 400-800mg/d 475 Efficacy (maintenance), tolerability 15.11.19 30.12.22 2022 completed None
NCT04325737 (2020) Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Japanese Male and Female Subjects With Schizophrenia DA801102, NCT04325737, jRCT2080225100 Sunovion/Sumitomo DB-RCT; 2 weeks (phase 1) Men/women 18-65 years with schizophrenia (stable, DSM-5) Cohort 1: Ulotaront (50mg/d to 100mg/d); Placebo; Cohort 2: Ulotaront (25mg/d to 100mg/d); Placebo 13 Tolerability, pharmacokinetics 31.03.20 07.08.20 2020 completed None
NCT04512066 (2020) A Trial of the Efficacy and the Safety of RO6889450 (Ralmitaront) vs Placebo in Patients With an Acute Exacerbation of Schizophrenia or Schizoaffective Disorder BP41743, NCT04512066, JPRN-jRCT2031200288 Hoffmann-La Roche DB-RCT; 4 weeks (up to 48 weeks extension) (phase II) Men/women 18-45 years with schizophrenia or schizoaffective disorder (acute, DSM-5) Ralmitaront 45mg/d; Ralmitaront 150mg/d; Risperidone 4mg/d; Placebo 287 Efficacy (acute), tolerability 08.09.20 21.06.22 2022 completed Efficacy, dropouts, side-effects
NCT04825860 (2021) A Clinical Trial to Evaluate the Efficacy and Safety of SEP-363856 in Acutely Psychotic People With Schizophrenia, Followed by an Open-label Extension Phase DA801201, NCT04825860, jRCT2071210003 Sunovion/Sumitomo DB-RCT; 6 weeks (and open label extension) (phase 2/3) Men/women 18-65 years with schizophrenia (acute, DSM-5) Ulotaront 50mg/d; Ulotaront 75mg/d; Placebo 480 Efficacy (acute), tolerability 29.03.21 30.06.25 NA ongoing None
NCT05402111 (2022) A Clinical Study That Will Assess How Food Moves Through the Stomach and Effects Blood Glucose Levels in Subjects With Schizophrenia Taking SEP-363856 or and Prior Antipsychotic (PA) Standard SEP361-124, NCT05402111 (2022) Sunovion/Sumitomo Open RCT two-period crossover; single dose (phase 1) Men/women 18-65 years with schizophrenia (stable, DSM-5) Ulotaront (25mg to 50mg); Prior antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole) 36 Pharmacokinetics, metabolic parameters 13.06.22 13.07.23 NA ongoing None
NCT05542264 (2022) A Clinical Study That Will Assess the Effect of SEP-363856 or Prior Antipsychotic (PA) Standard of Care on Body-weight Associated Parameters in Subjects With Schizophrenia SEP361-122, NCT05542264 Sunovion/Sumitomo DB-RCT; 2 weeks (phase 1) Men/women 18-65 years with schizophrenia (stable, DSM-5) Ulotaront; Prior antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole) 60 Metabolic parameters 15.11.22 23.10.23 NA ongoing None
NCT05593029 (2022) A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder 382-201-00001, NCT05593029 Sunovion/Sumitomo DB-RCT; 14 weeks (phase 2/3) Men/women 18-65 years with MDD (acute, DSM-5) Ulotaront; Placebo (add-on to antidepressants) 900 Efficacy (MDD), tolerability 09.11.22 45778 NA ongoing None
NCT05729373 (2023) A Clinical Study That Will Meaure How Well SEP-363856 Works and How Safe it is in Adults With Generalized Anixety Disorder SEP361-226, NCT05729373, EUCTR2022-502077-42-00 Sunovion/Sumitomo DB-RCT; 8 weeks (phase 2/3) Men/women 18-65 years with GAD (acute, DSM-5) Ulotaront (50-75mg/d); Placebo 464 Efficacy (GAD), tolerability 08.03.23 08.02.25 NA ongoing None
NCT05848700 (2023) A Clinical Study to Learn if SEP-363856 Has Physical Dependence in Adults With Schizophrenia SEP361-121, NCT05848700 Sunovion/Sumitomo DB-RCT; 10 weeks (phase 1) Men/women 18-65 years with schizophrenia (stable, DSM-5) Ulotaront continuation; Ulotaront discontinuation (switch to placebo) 60 Physical dependence, pharmacokinetics 21.06.23 23.02.24 NA ongoing None
Perini (2023) Effects of ulotaront on brain circuits of reward, working memory, and emotion processing in healthy volunteers with high or low schizotypy SEP361-104, NCT01972711 Sunovion/Sumitomo DB-RCT; single dose (phase 1) Men/women 18-45 years (high or low levels of schizotypy) Ulotaront 50mg; Amisulpride 400mg; Placebo 105 fMRI 41699 42186 2015 completed Dropouts, side-effects
SEP361-101 (in Galluppi 2021 and Chen 2022) A sensitive LC-MS/MS method for simultaneous quantification of ulotaront and its N-desmethyl metabolite in human plasma and application to a clinical study SEP361-101 Sunovion/Sumitomo SB-RCT; single ascending dose (phase I) Men >18 years Ulotaront (5mg to 125mg); Placebo 52 Pharmacokinetics NA NA 2021 completed None
Szabo (2023) A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy. SEP361-108 , NCT05015673 Sunovion/Sumitomo DB-RCT three-period crossover; 2 weeks (phase 1) Men/women 18-55 years with narcolepsy/cataplexy Ulotaront 25mg; Ulotaront 50mg; Placebo 18 Sleep parameters, pharmacokinetics, tolerability 05.06.14 26.05.15 2015 completed Dropouts, side-effects
Tsukada (2023) A randomized, single-dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia. SEP361-114, NCT04369391 Sunovion/Sumitomo DB-RCT three-period crossover; single dose (phase 1) Men/women 18-65 years with schizophrenia (stable, DSM-5) Ulotaront 150mg; Placebo; Moxifloxacin 400mg (ineligible for the review) 68 QTc interval, tolerability, pharmacokinetics 18.06.20 10.11.20 2020 completed Dropouts, side-effects

Table 1 Table of included studies.

Description of included studies

There were 25 eligible studies, which characteristics can be found in Table 1, with 20 studies (2147 participants) being completed and 5 studies being still ongoing up to 20.01.2024. There were usable data for this analysis from 9 studies (1711 participants), which enrolled adult populations across multiple countries and were funded by the industry manufactuing the TAAR1 agonists.

The usable studies compared single or multiple doses of two TAAR1 agonists (i.e., ulotaront or ralmitaront) with placebo or current antipsychotics (i.e., risperidone or amisulpride) in people with schizophrenia, Parkinson’s disease psyschosis, other mental health conditions (narcolepsy/cateplexy as sleep disorder) and healthy volunteers. Five studies used a parallel design to examine the efficacy and safety of multiple doses of TAAR1 agonists in psychosis within 3-13 weeks Four studies examining daily doses of TAAR1 agonists in adults with an acute episode of schizophrenia spectrum conditions for 4-6 weeks, 3 examined ulotaront (Koblan et al. 2020, NCT04072354 and NCT04092686) and 1 examined ralmitaront (NCT04512066). These studies used placebo as control group, and the 1 study on ralmitaront used also the antipsychotic risperidone as active comparator. One study comparing daily doses of ulotaront in Parkinson’s dissease psychosis to placebo for 4 weeks (Isaacson et al. 2023). Four studies examined the pharmacokinetics, safety and/or neuroimaging of single doses of TAAR1 agonists or multiple doses for up to 2 weeks: One study examining the effects of a single dose of 150mg ulotaront in *clinically stable adults with schizophrenia** on QTc interval within a day (Tsukada et al 2023). The study utilized a three-period crossover period comparing ulotaront with placebo and moxifloxacin (an antibiotic used as active comparator, not relevant for our analysis). Two studies examined the effects of single doses of ulotaront in healthy volunteers on sleep parameters (Hopkins et al 2021) or fMRI tasks (Perini et al 2023). Hopkins et al 2021 included two cohorts of crossover studies comparing two single doses of ulotaront with placebo. Perini et al 2023 was a parallel trial comparing ulotaront to placebo or the antipsychotic amisulpride on fMRI tasks relevant to reward, working memory and emotion processing in volunteers with high or low schizotypy traits. One study examined two single doses of ulotaront in adults with narcolepsy-cateplyxy compared to placebo using a three-period crossover design.

The following studies were unavailable: One study examined the efficacy and safety of ulotaront in comparison to placebo in adolescents with an acute episode schizophrenia (NCT04072354). This study had two parts with adults and adolescents. This study has been recently completed, and although some usable data in the adult population are available (see above), these are not available for the adolsecents. One study examined the long-term efficacy and safety of ulotaront in comparisong to the antispychotic quetiapine in adults with clinically stable schizophrenia (NCT04115319). The study should have been completed in 12.2022, and there are currently no usable data available. One study examined monotherapy or add-on treamtent with ralmitaront in comparison to placebo in adults with schizophrenia or schizoaffective disorder and predominant negative symptoms (NCT03669640). The study has been recently completed in 05.2023, and it has been reported to be failed, yet no usable data were available. Nine studies examined pharmacokinetics and safety of single or few multiple doses of ulotaront or ralmitaront in healthy volunteers (Fowler 2015, JapicCTI-194581, NCT02699372, SEP361-101, DA801002, NCT01940159, Koblan 2016, NCT04325737, NCT04865835).

The following studies are ongoing: - One study is examining the efficacy and safety of two ulotaront doses of 50mg/d and 75mg/d in comparison to placebo in adults with an acute episode of schizophrenia (NCT04825860). The study is expected to be completed in 06.2025. - Two studies are examining the efficacy and safety of ulotaront compared to placebo in other mental health conditions, i.e., adults with major depression (NCT05593029) and generalized anxiety disorder (NCT05729373). These trials are expected to be completed in 2025, and their safety data are relevant for this review.

Risk of bias assessment

The risk of bias of the studies was examined using the RoB2 tool for parallel and crossover studies for all outcomes. Here, we present the risk of bias of using the worst judgement of a domain across outcomes. It should be noted that when there were some concerns in only one of the domains, we assigned an overall low risk of bias according to our protocol.

Figure 2 Risk of bias of studies with usable data

All the studies were double-blind randomized controlled studies, with a low risk of bias in most cases in their respective domains of biases due to randomization, deviations from intended interventions, and outcome measurement. There were also no indications of selectively reported results; thus, the studies had a low risk of bias in their respective domains. Most of the studies had missing outcome data, but there was no clear indication that the missingness depended on the true value of the effects for most of the outcomes. Therefore, there were some concerns, except for Isaacson et al. 2023, which had a high risk of bias for efficacy outcomes but not for adverse events and other outcomes. Additionally, there were few differences in this domain across outcomes, such as a low risk for the outcome of dropouts. In terms of the three crossover studies, there was a low risk of bias in period and carry-over effects, except for some concerns in the three-period crossover study of Tsukada et al. 2023. Few differences across outcomes can be found in the overall judgment of the risk of bias for each study per outcome in the respective forest plots below.

Comparison 1: TAAR1 agonist vs placebo

Primary outcome: Overall symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks (primary timepoint)

Figure 3 Forest plot for overall symptoms (primary outcome) for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Positive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 4 Forest plot for positive symptoms for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Negative symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 5 Forest plot for negative symptoms for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Depressive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 6 Forest plot for depressive symptoms for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Cognitive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 7 Forest plot for cognitive impairment (measured with MMSE) for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Quality of life

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Functioning

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Response to treatment

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 8 Forest plot for response (>50% or 20% symptom reduction from baseline) for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Relapse

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Summary plot for efficacy outcomes

Figure 9 Summary plot for efficacy outcomes at 4-6 weeks for the comparison of TAAR1 agonists vs. placebo in the two populations of patients with an acute episode of schizophrenia and Parkinson’s disease psychosis. There were only available data for the timepoint of 3-13 weeks. The size of the points are proportional to the number of participants used in the analysis. SMD>0 correspond to more symptom improvement by TAAR1 agonists compared to placebo.

Secondary outcome: Dropouts due to any reason

Timepoint 1: 1 day - 2 weeks

Figure 10 Forest plot for dropouts due to any reason for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.Studies with no estimable effect size had 0 events in both arms.

Timepoint 2: 3 weeks - 13 weeks

Figure 11 Forest plot for dropouts due to any reason for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Dropouts due to adverse event

Timepoint 1: 1 day - 2 weeks

Figure 12 Forest plot for dropouts due to adverse event for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. Studies with no estimable effect size had 0 events in both arms.

Timepoint 2: 3 weeks - 13 weeks

Figure 13 Forest plot for dropouts due to adverse event for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Serious adverse event

Timepoint 1: 1 day - 2 weeks

Figure 14 Forest plot for serious adverse events for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. Studies with no estimable effect size had 0 events in both arms.

Timepoint 2: 3 weeks - 13 weeks

Figure 15 Forest plot for serious adverse events for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Death

Timepoint 1: 1 day - 2 weeks

There were available usable data from four studies (i.e., Hopkins et al 2021, Perini et al 2023, Szabo et al 2023 and Tsukada et al 2023) but all of them reported 0 deaths so that could not provide estimable effect sizes with the current approach.

Timepoint 2: 3 weeks - 13 weeks

Figure 16 Forest plot for death for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). Studies with 0 events in both arms could not provide estimable effect sizes with the current approach.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Any adverse event

Timepoint 1: 1 day - 2 weeks

Figure 17 Forest plot for any adverse events for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

Figure 18 Forest plot for any adverse event for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Anticholinergic symptoms

Timepoint 1: 1 day - 2 weeks

Figure 19 Forest plot for anticholinergic side-effects (i.e., dry mouth) for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Hypotension

Terms that were considered as reported in the trials: hypotension or orthostatic hypotension

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 20 Forest plot for hypotension for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Dizziness

Timepoint 1: 1 day - 2 weeks

Figure 21 Forest plot for dizziness for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

Figure 22 Forest plot for dizziness for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Nausea or vomiting

Timepoint 1: 1 day - 2 weeks

Figure 23 Forest plot for nausea or vomiting for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

Figure 24 Forest plot for nausea or vomitting for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

It should be noted that there appears to be some heterogeneity in the findings between ulotaront and ralmitaront. This heterogeneity may potentially be driven by the fact that ulotaront is also a 5-HT1A receptor partial agonist, which is associated with gastrointestinal symptoms.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: QTc prolongation

Timepoint 1: 1 day - 2 weeks

Figure 25 Forest plot for QTc prolongation for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. Studies with not estimable effect sizes had 0 events in both groups.

Timepoint 2: 3 weeks - 13 weeks

There were available data in Koblan et al 2020, which reported 0 events in both groups, so that an effect. size cannot be estimated with the current approach.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: QTc interval in msec

Timepoint 1: 1 day - 2 weeks

Figure 26 Forest plot for QTc interval in msec for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Weight increased

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 27 Forest plot for weight gain for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Weight in kg

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 28 Forest plot for weight change in kg for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Hyperprolactinemia

Timepoint 1: 1 day - 2 weeks

There were available data from one study Hopkins et al 2021 reporting 0 events in both arms so that an effect size cannot be estimated with the current approach.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Prolactin levels

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 29 Forest plot for prolactin levels in ng/ml for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). SD was imputed from the dataset of antipsychotic trials in Huhn et al 2021.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Akathisia

Terms considered included: restlessness (when was used to describe akathisia)

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 30 Forest plot for akathisia for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Extrapyramidal symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 31 Forest plot for extrapyramidal side effects (use of antiparkinsonian medication as a proxy) for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). Furthermore, narratively described findings in a conference abstract at ACNP 2023 regarding NCT04072354 and NCT04092686 mention that ulotaront did not differ in experimental side effects compared to placebo. Moreover, ulotaront was reported not to deteriorate movement symptoms in participants with Parkinson’s disease psychosis as measured with the Unified Parkinson Disease Rating Scale Part III.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Anxiety

Timepoint 1: 1 day - 2 weeks

There were usable data for one study Perini et al 2023, which reported 0 events in both groups so that an effect size could not be estimated with the current approach.

Timepoint 2: 3 weeks - 13 weeks

Figure 32 Forest plot for anxiety as adverse event for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Agitation

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 33 Forest plot for agitation for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Headache

Timepoint 1: 1 day - 2 weeks

Figure 34 Forest plot for headache for the comparison of TAAR1 agonist vs. placebo at 1 day to 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

Figure 35 Forest plot for headache for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Sedation

Terms that were considered as reported in the trials: fatigue, sedation, somnolence

Timepoint 1: 1 day - 2 weeks

Figure 36 Forest plot for sedation for the comparison of TAAR1 agonist vs. placebo at 1 day to 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

Figure 37 Forest plot for sedation for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Insomnia

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 38 Forest plot for insomnia for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Summary plot for dropouts and side-effects

Figure 39 Summary forest plot for dropouts and side-effects for the comparison of TAAR1 agonists compared to placebo and for the two timepoints with usable data. It should be noted that different populations have been pooled in the analysis of dropouts and adverse events including schizophrenia, Parkinson’s disease psychosis, narcolepsy-cateplexy and healthy volunteers. The size is proportional to the number of participants in the analysis. OR>1 corresponds to more events with TAAR1 agonists compared to placebo.

Secondary outcome: Neurobiological measures relevant relevant to psychosis such as dopaminergic, glutamatergic and serotonergic signalling

Timepoint 1: 1 day - 2 weeks

No usable data were available from RCTs. However, Perini et al. 2023 examined the effects of single doses of ulotaront compared to placebo in volunteers with low or high schizotypy traits on fMRI of BOLD responses to neuropsychological tasks that could be considered only as weak proxies for neurotransmitter signaling. Thus, they were not quantitatively further analyzed but narratively described in this iteration of the review. The primary outocme of this study was the response of the changes in BOLD responses in the striatum during the anticipation phase of the monetary incentive delay (MID) task and interaction with schizotypy traits. This was potentially selected a posteriori given that the complete protocol was not available and the

Specifically, ulotaront, compared to placebo, appeared to reverse increased BOLD responses in the striatum during the anticipation phase of the monetary incentive delay (MID) task in participants with high schizotypy traits compared to those with low schizotypy traits. This was the primary outcome of this study, which selection was described to be due to its relevance to reward processing and increased dopamine synthesis capacity, thus serving as a weak proxy for ulotaront’s effects on decreasing presynaptic dopamine synthesis capacity. However, there is possibility that this outcome was selected a posteriori due to significant findings and the protocol of the study was not available and the clinicaltrials.gov did not specify a primary outcome. Thus, there is the possibility of risk of bias of selected reported outcome. There were also differences between ulotaront and placebo in some other fMRI and neuropsychological measures, including that ulotaront compared to placebo decreasing the performance in N-back tasks (working memory measure) and emotional test battery ().

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Comparison 2: TAAR1 agonist vs antipsychotic

Primary outcome: Overall symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks (primary timepoint)

Figure 40 Forest plot for overall symptoms (primary outcome) for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Positive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 41 Forest plot for positive symptoms for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Negative symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 42 Forest plot for negative symptoms for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Depressive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 43 Forest plot for depression symptoms for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Cognitive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Quality of life

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Functioning

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Response to treatment

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 44 Forest plot for response to treatment (>50% symptom reduction from baseline) for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Relapse

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Summary plot for efficacy outcomes

Figure 45 Summary plot for efficacy outcomes at 4 weeks for the comparison of TAAR1 agonists versus antipscyhotcs in patients with an acute episode of schizophrenia. There were only data for the timepoint of 3-13 weeks. SMD>0 correspond to more symptom improvement by TAAR1 agonists compared to placebo.

Secondary outcome: Dropouts due to any reason

Timepoint 1: 1 day - 2 weeks

Figure 46 Forest plot for dropouts due to any reason for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

Figure 47 Forest plot for dropouts due to any reason for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Dropouts due to adverse event

Timepoint 1: 1 day - 2 weeks

There were usable data in Perini et al 2023, whcih reported 0 events in both groups and an effect size cannot be estimated with the current approach.

Timepoint 2: 3 weeks - 13 weeks

Figure 48 Forest plot for dropouts due to adverse events for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Serious adverse event

Timepoint 1: 1 day - 2 weeks

Figure 49 Forest plot for serious adverse events for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

Figure 50 Forest plot for serious adverse events for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Death

Timepoint 1: 1 day - 2 weeks

There were usable data in Perini et al 2023, whcih reported 0 events in both groups and an effect size cannot be estimated with the current approach.

Timepoint 2: 3 weeks - 13 weeks

There were usable data in NCT04512066, whcih reported 0 events in both groups and an effect size cannot be estimated with the current approach.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Any adverse event

Timepoint 1: 1 day - 2 weeks

Figure 51 Forest plot for any adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

Figure 52 Forest plot for any adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Anticholinergic symptoms

Terms that were considered as reported in the trials: dry mouth (no other relevant anticholinergic side-effects were reported such as urinary retention, constipation, mydriasis or blurred vision)

Timepoint 1: 1 day - 2 weeks

Figure 53 Forest plot for anticholinergic side effects (e.g., dry mouth in this study) for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Hypotension

Terms that were considered as reported in the trials: hypotension or orthostatic hypotension

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Dizziness

Timepoint 1: 1 day - 2 weeks

Figure 54 Forest plot for dizziness for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Nausea or vomiting

Terms that were considered as reported in the trials: nausea, vomiting, emesis

Timepoint 1: 1 day - 2 weeks

Figure 55 Forest plot for nausea or vomitting for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.It should be noted that the study Perini et al 2023 examined ulotaront that is also a partial agonsit of 5-HT1A causing potentially gastrointestinal side-effects. In comparison, ralmitaront is not a partial agonist of the 5-HT1A receptor.

Timepoint 2: 3 weeks - 13 weeks

Figure 56 Forest plot for nausea or vomitting for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). It should be noted that the study NCT04512066 examined ralmitaront, which compared to ulotaront is not a partial agonist of the 5-HT1A receptor that can be associated with gastrointestinal side effects.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: QTc prolongation

Terms that were considered as reported in the trials: QTc prolongation above ≥450 msec or an increase of ≥60 msec (any threshold was eligible)

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: QTc interval in msec

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Weight increased

Terms considered included: any weight increase, weight increase >7%

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 57 Forest plot for weight increase for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Weight in kg

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Hyperprolactinemia

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Prolactin levels

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Akathisia

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Exrapyramidal symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Anxiety

Timepoint 1: 1 day - 2 weeks

Figure 58 Forest plot for anxiety as adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

Figure 59 Forest plot for anxiety as adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Agitation

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 60 Forest plot for agitation for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Headache

Timepoint 1: 1 day - 2 weeks

Figure 61 Forest plot for headache as adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

Figure 62 Forest plot for headache for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Sedation

Terms that were considered as reported in the trials: fatigue, sedation, somnolence

Timepoint 1: 1 day - 2 weeks

Figure 63 Forest plot for sedation for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Secondary outcome: Insomnia

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 64 Forest plot for insomnia for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).

Timepoint 3: > 13 weeks

No usable data available from RCT.

Summary plot for the side-effects

Figure 65 Summary forest plot for dropouts and side-effects for the comparison of TAAR1 agonists compared to antipsychotics and for the two timepoints with usable data. There were data for single doses of ralmitaront versus amisulpride in healthy volunteers at 1 day, and ulotaront versus risperidone in acute schizophrenia or schizoaffective disorder at 4 weeks. The size of the points is proporitonal tothe number of participants. OR>1 corresponds to more events with TAAR1 agonists compared to placebo.

Secondary outcome: Neurobiological measures relevant relevant to psychosis such as dopaminergic, glutamatergic and serotonergic signalling

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

Subgroup analyses and meta-regressions

There were less than 5 studies available for the analyses of the primary outcome, precluding the exploration of potential reasons of heterogeneity with subgroup analyses and meta-regressions.

Nevertheless, we explored potential differences between ulotaront and ralmitaront in improving overall symptoms of acute schizophrenia, and potential dose-effects by plotting the effect sizes for each fixed-dose level of TAAR1 agonist compared to placebo. However, we did not conduct any formal subgroup test or dose-response meta-analysis due to the limited number of studies.

Moreover, it should be noted that we presented the effect sizes in each specific subgroup of participants for all outcomes, but we did not perform a formal subgroup test

Exploration of differences between ulotaront and ralmitaront in their effects on overall symptoms of acute schizophrenia.

Figure 66 Forest plot presenting the effects of ulotaront and ralmitaront compared to placebo on overall symptoms in acute schizophrenia at 4-6 weeks separately.

Exploration of dose-effects of ulotaront and ralmitaront on overall symptoms of acute schizophrenia

Figure 67 Effect sizes for each dose level of ulotaront and ralmitaront compared to placebo in improving overall symptoms of acute schizophrenia at 4-6 weeks are presented separately. The findings of each study are presented separately, and the effect sizes were corrected for using the same control condition in each study. It should be noted that Koblan 2020 was a two-arm flexible dose study, and its effect size is placed in the middle of the range of the administered dose (50mg/d to 75mg/d)

In the fixed-dosing studies, higher doses (i.e., ulotaront 100mg/d and ralmitaront 100mg/d) may be associated with more improvement compared to smaller doses. However, the effect sizes at these high doses still appear to be small, with a standardized mean difference (SMD) of approximately 0.2. In the flexible dosing study by Koblan et al. 2020, which utilized doses of ulotaront up to 75mg/d, small-to-medium effect sizes were observed. Importantly, the available data are limited. Therefore, the findings are inconclusive.

Sensitivity analyses

We did not conduct the following sensitivity analyses for the primary outcome due to the limited data: 1) Restricting the analysis to studies with low risk of bias, since there were 4 studies with low risk of bias in acute schizophrenia, and 1 study with high risk of bias in Parkinson’s disease psychosis (1 study with high risk of bias). 2) Excluding imputed data, since no imputed data were used in the analysis of the primary outcome.” There were no imputed data in the analysis of the primary outcome.

Due to the limited number of studies, we also presented a fixed-effects model for all outcomes in addition to the random-effects model to assess the robustness of the findings. The findings were robust in the majority of cases. For the primary outcome in the meta-analysis of 4 studies in acute schizophrenia, the point estimate of the effect sizes did not differ between random- and fixed-effects (SMD=0.15 and 0.13, respectively), but the 95% CI in the fixed-effects model was narrower, excluding the null effect (95% CI: -0.05, 0.34, and 0.02, 0.05, respectively). Nonetheless, the interpretation of the findings that TAAR1 agonists have little to no effect compared to placebo in improving overall symptoms does not change

Reporting bias

Reporting bias was evaluated using the ROB-ME tool, taking into account the usable data from the eligible studies identified in the search, the comprehensiveness of the search, and potential patterns of missingness and small-study effects. We followed the algorithm to assign a low or high risk of reporting bias, or to express some concerns, by answering signaling questions related to the domains mentioned above.

Funnel plots and examination of small-study effects

There were insufficient data for the primary outcome but also other outcomes (i.e., fewer than 10 studies) to examine small-study effects with funnel plots. Thus, we cannot explore the pattern of missing evidence or conduct sensitivity analysis to explore the potential impact of the missing evidence. Thus, we replied the following signalling questions as ROB-ME-4.7: “probably no” and ROB-ME-4.8: “probably no”.

Coverage of the search strategy

We conducted a comprehensive search for both published and unpublished studies in multiple electronic databases, supplemented by manual searches of the reference lists of included studies and previous reviews. Screening was carried out by at least two independent reviewers. All studies identified in the search were conducted by the pharmaceutical industry. Although we contacted them, we have not received additional data for the first iteration. Considering that all eligible studies are experimental and were conducted recently, it is expected that most, if not all, have been registered, thus facilitating their detection during searches in clinical trial registries. Nonetheless, it’s possible that small phase I studies focusing on pharmacokinetics may not have been registered and could therefore have been overlooked. Consequently, we do not anticipate that our search has missed any major or significant studies (ROB-ME-3.1: “no”, ROB-ME-3.2: “probably yes”, ROB-ME-3.3:“probably yes”, ROB-ME-4.5: “no”).

Results matrix and ROB-ME evaluation

We identified the total number of eligible and completed studies, with or without usable data, that could contribute to dropout and safety data for each comparison (as shown in Table 1 and Table 2): 1) There were 12 studies with 626 participants for the comparison of TAAR1 agonists versus placebo over a period of 1 day to 2 weeks. 2) There were 2 studies with 100 participants for the comparison of TAAR1 agonists versus placebo over the same duration. 3) For the comparison of TAAR1 agonists versus placebo over 3-13 weeks, there were 6 studies involving 1550 participants, including also 1 study (NCT03669640) focusing predominantly on negative symptoms. 4) Finally, it should be noted that one study (NCT04115319) with 475 participants could contribute to the comparison of TAAR1 agonists versus other antipsychotics for periods exceeding 13 weeks. However, no usable data for this analysis were available from any other study.

The results matrix for the eligible studies, which were identified in the search, for all outcomes with usable data from at least one study, can be found below in Table 2.

Timepoint Study name Population Comparison Sample size Overall symptoms Response Positive symptoms Negative symptoms Depressive symptoms Cognitive impairment Dropouts due to any reason Dropouts due to adverse events Any adverse event Serious adverse event Mortality due to any cause Nausea or vomitting Weight change (kg) Weight increase (dichotomous) Prolactin levels (ng/ml) Prolactin (dichotomous) Extrapyramidal side-effects Akathisia Agitation Anxiety Sedation Insomnia Headache QTc interval (msec) QTc prolongtion (dichotomous) Hypotension Dizziness Anticholinergic
1 day to 2 weeks DA801002 (in Galluppi et al. 2021) Volunteers TAAR1 agonists vs. placebo 16 na na na na na na ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) na na ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics)
1 day to 2 weeks Fowler et al. 2015 Volunteers TAAR1 agonists vs. placebo 49 na na na na na na ? (reported as well tolerated without relevant findings, no further information) ? (reported as well tolerated without relevant findings, no further information) ? (reported as well tolerated without relevant findings, no further information) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) na na ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics)
1 day to 2 weeks Hopkins et al. 2021 Volunteers TAAR1 agonists vs. placebo 24 na na na na na na na na < (prolactin elevation as dichotomous outcome) ? (reported as generally safe and well tolerated) ? (reported as generally safe and well tolerated) ? (reported as generally safe and well tolerated, no changes in vital signs or physical examination) ? (reported as generally safe and well tolerated, no changes in vital signs or physical examination) ? (reported as generally safe and well tolerated, no changes in vital signs or physical examination) ? (reported as generally safe and well tolerated, no changes in vital signs or physical examination) < (reported as dichotomous outcome) ? (reported as generally safe and well tolerated, no changes in vital signs or physical examination) ? (reported as generally safe and well tolerated, no changes in vital signs or physical examination) ? (reported as generally safe and well tolerated, no changes in vital signs or physical examination)
1 day to 2 weeks JapicCTI-194581 Volunteers TAAR1 agonists vs. placebo 64 na na na na na na ? ? ? ? ? ? na na ? ? ? ? ? ? ? ? ? ? ? ? ? ?
1 day to 2 weeks Koblan et al. 2016 Schizophrenia (clinically stable) TAAR1 agonists vs. placebo 48 na na na na na na ? ? ? ? ? ? na na ? ? ? ? ? ? ? ? ? ? ? ? ? ?
1 day to 2 weeks NCT01940159 Schizophrenia (clinically stable) TAAR1 agonists vs. placebo 48 na na na na na na ? ? ? ? ? ? na na ? ? ? ? ? ? ? ? ? ? ? ? ? ?
1 day to 2 weeks NCT02699372 Volunteers TAAR1 agonists vs. placebo 164 na na na na na na ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters)
1 day to 2 weeks NCT04325737 Schizophrenia (clinically stable) TAAR1 agonists vs. placebo 13 na na na na na na ? ? ? ? ? ? na na ? ? ? ? ? ? ? ? ? ? ? ? ? ?
1 day to 2 weeks Perini et al. 2023 Volunteers TAAR1 agonists vs.placebo vs. antipsychotics 105 na na na na na na na na ? (no clinically meaningul changes in safety parameters, unclear if measured) ? (no clinically meaningul changes in safety parameters, unclear if measured) ? (no clinically meaningul changes in safety parameters) ? (no clinically meaningul changes in safety parameters) ? (no clinically meaningul changes in safety parameters) ? (no clinically meaningul changes in safety parameters) ? (no clinically meaningul changes in safety parameters) ? (no clinically meaningul changes in safety parameters, unclear if measured) ? (no clinically meaningul changes in safety parameters, unclear if measured) ? (no clinically meaningul changes in safety parameters)
1 day to 2 weeks SEP361-101 (in Galluppi et al. 2021 and Chen et al. 2022) Volunteers TAAR1 agonists vs. placebo 52 na na na na na na ? (reported as well tolerated without relevant findings, no further information) ? (reported as well tolerated without relevant findings, no further information) ? (reported as well tolerated without relevant findings, no further information) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) na na ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics) ? (no information, single dose study focusing on pharmacokinetics)
1 day to 2 weeks Szabo (2023) Narcolepsy-cataplexy TAAR1 agonists vs. placebo 18 na na na na na na ? (no clearly described under which treatments) ? (2 patients had dropped out due to nausea, but uclear under which treatment) ? (4 patients had nausea but uclear under which treatment) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurmenet, laboratory safety parameters) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (2 patients had somnolence but uclear under which treatment) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations) ? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)
1 day to 2 weeks Tsukada et al. 2023 Schizophrenia (clinically stable) TAAR1 agonists vs. placebo 68 na na na na na na ? (no clearly described under which treatments) na na ? (no changes in vital signs, ulotaront well-tolerated) ? (no changes in vital signs, ulotaront well-tolerated) ? (no changes in vital signs, ulotaront well-tolerated) ? (no changes in vital signs, ulotaront well-tolerated) ? (no changes in vital signs, ulotaront well-tolerated) ? (no changes in vital signs, ulotaront well-tolerated) ? (no changes in vital signs, ulotaront well-tolerated) ? (no changes in vital signs, ulotaront well-tolerated) ? (no changes in vital signs, ulotaront well-tolerated) ? (no changes in vital signs, ulotaront well-tolerated)
1 day to 2 weeks NCT05402111 Schizophrenia (clinically stable) TAAR1 agonists vs. antipsychotics 36 na na na na na na ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
3-13 weeks Isaacson et al. 2023 Parkinson’s disease psychosis TAAR1 agonists vs. placebo 39 < (probably not measured) < (probably not measured) ? (no information, no clinically meaningul changes in ECG, laboratory values) ? (no information, no clinically meaningul changes in ECG, laboratory values) ? (no information, no clinically meaningul changes in ECG, laboratory values) NA < (measured with UPDRS paRT III scale, no differences with placebo) < (measured with UPDRS paRT III scale, no differences with placebo) ? (neuropsychiatric events seemed to more frequent in ulotaront vs. placebo, including hallucinations and confusational state) ? (neuropsychiatric events seemed to more frequent in ulotaront vs. placebo, including hallucinations and confusational state) ? ? (no information, no clinically meaningul changes in ECG, laboratory values) ? (no information, no clinically meaningul changes in ECG, laboratory values) ?
3-13 weeks Koblan et al. 2020 Schizophrenia (acute) TAAR1 agonists vs. placebo 245 ? (probably not measured at the randomized phase) < (reported as continuous) < (reported as dichotomous outcome) ? ? ?
3-13 weeks NCT04072354 Schizophrenia (acute) TAAR1 agonists vs. placebo 463 X X X ? (probably not measured) ? ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) < (frequency of extapyramidal side-effects was low and similar to placebo) < (frequency of extapyramidal side-effects was low and similar to placebo) ? (no infromation, NNH for all adverse events >=10) ? (reported as common, NNH>=10) NA ? (reported as common, NNH>=10) ? (reported as common, NNH>=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10)
3-13 weeks NCT04092686 Schizophrenia (acute) TAAR1 agonists vs. placebo 462 ✓ (adult) / ? (adolescent) X X X ? (probably not measured) ? ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) NA ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) < (frequency of extapyramidal side-effects was low and similar to placebo) < (frequency of extapyramidal side-effects was low and similar to placebo) ? (no infromation, NNH for all adverse events >=10) ? (reported as common, NNH>=10) NA ? (reported as common, NNH>=10) ? (reported as common, NNH>=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10) ? (no infromation, NNH for all adverse events >=10)
3-13 weeks NCT04512066 Schizophrenia or schizoaffective disorder (acute) TAAR1 agonists vs.placebo vs. antipsychotics 287 ? < (reported as dichotomous outcome) ? ? ? ? ? ? ? ? ? ?
3-13 weeks NCT03669640 Schizophrenia (negative symptoms) TAAR1 agonists vs. placebo 128 ? ? ? X (failed trial focusing on negative symptoms) ? ? (probably not measured) ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
> 13 weeks NCT04115319 Schizophrenia (clinically stable) TAAR1 agonists vs. antipsychotics 475 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?

Table 2 Results matrix for the primary outcome. ✓: A study result is available for inclusion in the meta-analysis.; ~:No study result is available for inclusion in the meta-analysis, for a reason unrelated to the P value, magnitude or direction of the result.; ?: Unclear whether an eligible study result was generated or unclear reason of missing evidence. Narrative descriptions of the effects of drugs as reported in the studies are mentioned here to facilitate the judgement of regarding the reasong of missigness. *NCT04072354 included two parts, i.e., adults (sample size 435) and adolescents (sample size unclear but it was probably 28; planned 90). It should be noted that all of the other studies included adult populations. na: not applicable for this outcome (e.g., efficacy outcomes in healthy volunteers or after a single dose in stable patients).

Data were available for all eligible studies concerning the primary outcome, i.e., answers to the ROB-ME signalling question 4.1: “no”, ROB-ME-4.3: “yes” for adolescents, ROB-ME-4.4: “no”, thus leading to low risk of reporting bias - considering also the comprehensiveness of the search.

The results matrix in Table 2 could also apply to the secondary efficacy outcomes in acute psychosis, although some studies did not have usable data for these outcomes. Specifically, the two phase III trials, NCT04092686 and NCT04072354, did not report effects on symptom domains. Consequently, these analyses would be prone to bias due to missing evidence (ROB-ME-4.1: “yes”, ROB-ME-4.2: “yes”, thus leading to high risk of reporting bias).

The reasons for the missingness of data for these outcomes can be unclear, but in most cases, it is due to either not being measured or not reported for reasons other than their P-values, magnitude, and direction of effects, yet this cannot be excluded. Therefore, we employed, as a general rule, the following approach in response to ROB-ME-4.1: “no” (as none was generally considered to have reported usable data for these outcomes due to their P-value, magnitude, or direction), ROB-ME-4.3: ‘yes’, ROB-ME-4.4: ‘yes’ if less than 50% of the participants had usable data, suggesting that the findings could notably change if the missing data had been added to the analysis. The cutoff of 50% of the participants was selected to balance out that in most cases, the findings were not missing due to unfavorable findings (see Table 2) but also to consider the possibility that the findings may be likely to change with the addition of missing evidence, given the small number of studies and participants in their estimates. In this situation, we assigned a high risk of reporting bias, but the impact of this on the magnitude and direction of the findings can be unclear. If there were data from at least 50% of the participants, we responded to ROB-ME-4.4: ‘no’, leading to some concerns given that ROB-ME-4.5: “no” see above, and patterns of missing evidence or sensitivity analyses could not be conducted.

Summary of evidence

Approach to evaluate the confidence in the evidence

For each comparison, outcome and timepoint, we presented the summary of the evidence by presenting the summary of the association, biases due to study limitations, biasesd due to reporting bias, biases due to indirectness and other biases. [[[[ We assigned “low risk”, “some concerns” and “high risk” in the domains of biases and presented the potential impact on the magnitude and direction of effects. We also assigned an overall judgement in the confidence of the evidence that could be “high”, “moderate”, “low” or “very low”.]]]—>Use GRADE

Summary of the association: We presented the number of studies (N), participants (n) contributing to the analysis, the point estimates and 95% confidence intervals for both random- and fixed-effects models. We also made a statement about dose-effects for the primary outcome (Figure 67).

Biases due to study limitations: The majority of the studies had a low risk of bias, or at most, some concerns across domains and outcomes, except for one small study (Isaacson et al., 2023) with a high risk of bias due to missing outcome data for some of the outcomes. Thus, we assigned “low risk” except for “high risk” when findings were based on the latter single study.

Biases due to reporting bias: We used the approach mentioned above to assigned “low risk”, “some concerns” or “high risk”.

Biases due to indirectness: We assigned “no concerns” in indirectness, as there were no issues related to population, interventions, control conditions, outcomes, or settings in the analysis of efficacy outcomes using data from clinical trials in adults with an acute episode of schizophrenia or Parkinson’s disease psychosis. However, potential indirectness in terms of population characteristics may exist in the analysis of other outcomes. This is because we pooled data from diverse populations, including those with schizophrenia spectrum disorders, Parkinson’s disease psychosis, narcolepsy-cataplexy, and healthy volunteers. Although the majority of adverse events might not vary across these groups, we considered “some concerns” in indirectness when the analyses included fewer than 50% of participants with schizophrenia. This is because schizophrenia is the primary population to which these findings would be applied. Nevertheless, the impact on the magnitude and direction of the effects can be unclear.

Other biases: We considered additional biases, such as potential factors that could impact the magnitude and direction of the findings. Specifically, we considered “some concerns” for other biases for the primary outcome and response to treatment in adults with an acute episode of schizophrenia due to potential problems in the execution of trials during COVID-19 (NCT0407254, NCT04092686, NCT04512066). The two phase III trials of ulotaront, NCT04072354 and NCT04092686, had high placebo effects of about 14 points and 19 points reduction in PANSS total scores (compared to a mean of 6 points in other antipsychotic trials), suggesting that potential factors associated with placebo effects could have diluted effect sizes and underestimated the effects. A conference abstract at ACNP 2024 reported that pooled analyses of these two trials using participants enrolled before COVID-19 found effect sizes similar to the phase II trial (Koblan 2019). A potential explanation, among others, could be baseline inflation due to recruitment pressure during the COVID-19 pandemic. Thus, the possibility that the findings have been underestimated cannot be excluded.

[[[[[Confidence in the evidence: We assigned an overall judgment on the confidence in the estimates by considering the above domains. We started with “high” confidence as we used data from randomized controlled trials, and we downgraded the confidence by one level for “some concerns” and two for “high risk” of bias in the above domains. Moreover, we considered potential imprecision in the summary of the association, taking into consideration the 95% CI (using a cutoff of trivial effects |SMD|=0.1 and OR=1/2 and 0.83) and sample size (cutoff of 800 participants based on a power calculation with a power of 80% to find SMD=0.2), as well as potential heterogeneity, considering a visual inspection of forest plots (due to the limited number of studies to estimate tau-squared).]]]]] —> Use GRADE????

Summary of evidence tables

Summary of evidence table for the comparison of TAAR1 agonists versus placebo for efficacy outcomes in adults with an acute episode of schizophrenia

Outcome Timepoint Summary of the association Bias due to study limitations Bias due to. Reporting bias Bias due to indirectness Bias due to other reasons
Overall symptoms (PANSS total) - primary outcome (Figure 3) 4-6 weeks N=4, n=1291; Random-effects: SMD=0.15, 95%CI: -0.05, 0.34; Fixed-effecs: SMD=0.13, 95%CI: 0.02, 0.25; Dose-effects: Higher doses (ulotaront 100mg/d and ralmitaront 150mg/d) may have larger effects, but the findings are inconclusive. Low risk: All studies had overall low risk of bias. Low risk: All eligible studies had usable data. Low risk: No clear indication of indirectness. Some concerns: Three trials were conducted during COVID-19 (2 in ulotaront, 1 in ralmitaront), which could be associated with factors related to small effect sizes. A pooled analysis of the two Phase III ulotaront trials, using only the participants enrolled before COVID-19, showed effect sizes like the Phase II ulotaront trial. This may have underestimated the effects.
Response to treatment (≥50% or ≥20% reduction in PANSS total) (Figure 8) 4-6 weeks N=4, n=1357; Random-effects: 23.7% vs. 18.7%, OR=1.35, 95%CI: 0.86, 2.12; Fixed-effecs: OR=1.39, 95%CI: 1.04, 1.86 Low risk: All studies had overall low risk of bias Low risk: All eligible studies had usable data Low risk: No clear indication of indirectness Some concerns: Three trials were conducted during COVID-19 (2 in ulotaront, 1 in ralmitaront), which could be associated with factors related to small effect sizes. A pooled analysis of the two Phase III ulotaront trials, using only the participants enrolled before COVID-19, showed effect sizes like the Phase II ulotaront trial. This may have underestimated the effects.
Positive symptoms (PANSS positive subscale/factor) (Figure 4) 4 weeks N=2, n=399; Random-effects: SMD=0.23, 95%CI: 0.03, 0.43; Fixed-effecs: SMD=0.23, 95%CI: 0.03, 0.43 Low risk: All studies had overall low risk of bias High risk: 50% of eligible studies and 28.9% of participants had usable data. 2 failed phase III trials did not have usable data. This may have overestimated the effects. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Negative symptoms (PANSS negative subscale/factor) (Figure 5) 4 weeks N=2, n=399; Random-effects: SMD=0.23, 95%CI: -0.01, 0.48; Fixed-effecs: SMD=0.24, 95%CI: 0.04, 0.44 Low risk: All studies had overall low risk of bias High risk: 50% of eligible studies and 28.9% of participants had usable data. 2 failed phase III trials did not have usable data. This may have overestimated the effects. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Depressive symptoms (PANSS anxiety/depression factor) (Figure 6) 4 weeks N=2, n=399; Random-effects: SMD=0.17, 95%CI: -0.06, 0.39; Fixed-effecs: SMD=0.17, 95%CI: -0.03, 0.37 Low risk: All studies had overall low risk of bias High risk: 50% of eligible studies and 28.9% of participants had usable data. 2 failed phase III trials did not have usable data. This may have overestimated the effects. Low risk: No clear indication of indirectness Low risk: No indication of other biases

Summary of evidence table for the comparison of TAAR1 agonists versus placebo for efficacy outcomes in adults with an acute episode of schizophrenia

Outcome Timepoint Summary of the association Bias due to study limitations Bias due to. Reporting bias Bias due to indirectness Bias due to other reasons
Overall symptoms (PANSS total) - primary outcome (Figure 3) 4-6 weeks N=4, n=1291; Random-effects: SMD=0.15, 95%CI: -0.05, 0.34; Fixed-effecs: SMD=0.13, 95%CI: 0.02, 0.25; Dose-effects: Higher doses (ulotaront 100mg/d and ralmitaront 150mg/d) may have larger effects, but the findings are inconclusive. Low risk: All studies had overall low risk of bias. Low risk: All eligible studies had usable data. Low risk: No clear indication of indirectness. Some concerns: Three trials were conducted during COVID-19 (2 in ulotaront, 1 in ralmitaront), which could be associated with factors related to small effect sizes. A pooled analysis of the two Phase III ulotaront trials, using only the participants enrolled before COVID-19, showed effect sizes like the Phase II ulotaront trial. This may have underestimated the effects.
Response to treatment (≥50% or ≥20% reduction in PANSS total) (Figure 8) 4-6 weeks N=4, n=1357; Random-effects: 23.7% vs. 18.7%, OR=1.35, 95%CI: 0.86, 2.12; Fixed-effecs: OR=1.39, 95%CI: 1.04, 1.86 Low risk: All studies had overall low risk of bias Low risk: All eligible studies had usable data Low risk: No clear indication of indirectness Some concerns: Three trials were conducted during COVID-19 (2 in ulotaront, 1 in ralmitaront), which could be associated with factors related to small effect sizes. A pooled analysis of the two Phase III ulotaront trials, using only the participants enrolled before COVID-19, showed effect sizes like the Phase II ulotaront trial. This may have underestimated the effects.
Positive symptoms (PANSS positive subscale/factor) (Figure 4) 4 weeks N=2, n=399; Random-effects: SMD=0.23, 95%CI: 0.03, 0.43; Fixed-effecs: SMD=0.23, 95%CI: 0.03, 0.43 Low risk: All studies had overall low risk of bias High risk: 50% of eligible studies and 28.9% of participants had usable data. 2 failed phase III trials did not have usable data. This may have overestimated the effects. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Negative symptoms (PANSS negative subscale/factor) (Figure 5) 4 weeks N=2, n=399; Random-effects: SMD=0.23, 95%CI: -0.01, 0.48; Fixed-effecs: SMD=0.24, 95%CI: 0.04, 0.44 Low risk: All studies had overall low risk of bias High risk: 50% of eligible studies and 28.9% of participants had usable data. 2 failed phase III trials did not have usable data. This may have overestimated the effects. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Depressive symptoms (PANSS anxiety/depression factor) (Figure 6) 4 weeks N=2, n=399; Random-effects: SMD=0.17, 95%CI: -0.06, 0.39; Fixed-effecs: SMD=0.17, 95%CI: -0.03, 0.37 Low risk: All studies had overall low risk of bias High risk: 50% of eligible studies and 28.9% of participants had usable data. 2 failed phase III trials did not have usable data. This may have overestimated the effects. Low risk: No clear indication of indirectness Low risk: No indication of other biases

Table 3 Summary of evidence table for the comparison of TAAR1 agonists versus placebo for efficacy outcomes in adults with an acute episode of schizophrenia. There were data for ulotaront and ralmitaront.

Summary of evidence table for the comparison of TAAR1 agonists versus antipsychotics for efficacy outcomes in adults with an acute episode of schizophrenia

Outcome Timepoint Summary of the association Bias due to study limitations Bias due to. Reporting bias Bias due to indirectness Bias due to other reasons
Overall symptoms (PANSS total) – primary outcome (Figure 40) 4 weeks N=1, n=156; SMD=-0.53, 95%CI: -0.86, -0.2 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Response to treatment (≥50% or ≥20% reduction in PANSS total) (Figure 44) 4 weeks N=1, n=214; 7.9% vs. 13.5%, OR=0.55, 95%CI: 0.22, 1.35 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Positive symptoms (PANSS positive subscale/factor) (Figure 41) 4 weeks N=1, n=156; SMD=-0.55, 95%CI: -0.89, -0.22 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Negative symptoms (PANSS negative subscale/factor) (Figure 42) 4 weeks N=1, n=156; SMD=-0.13, 95%CI: -0.46, 0.19 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Depressive symptoms (PANSS anxiety/depression factor) (Figure 43) 4 weeks N=1, n=156; SMD=-0.23, 95%CI: -0.56, 0.1 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases

Table 3 Summary of evidence table for the comparison of TAAR1 agonists versus antipsychotics for efficacy outcomes in adults with an acute episode of schizophrenia. There were data from a single study for ralmitaront versus risperidone.

Summary of evidence table for the comparison of TAAR1 agonists versus placebo for efficacy outcomes in Parkinson’s disease psychosis

Outcome Timepoint Summary of the association Bias due to study limitations Bias due to. Reporting bias Bias due to indirectness Bias due to other reasons
Overall symptoms (PANSS total) – primary outcome (Figure 40) 4 weeks N=1, n=156; SMD=-0.53, 95%CI: -0.86, -0.2 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Response to treatment (≥50% or ≥20% reduction in PANSS total) (Figure 44) 4 weeks N=1, n=214; 7.9% vs. 13.5%, OR=0.55, 95%CI: 0.22, 1.35 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Positive symptoms (PANSS positive subscale/factor) (Figure 41) 4 weeks N=1, n=156; SMD=-0.55, 95%CI: -0.89, -0.22 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Negative symptoms (PANSS negative subscale/factor) (Figure 42) 4 weeks N=1, n=156; SMD=-0.13, 95%CI: -0.46, 0.19 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Depressive symptoms (PANSS anxiety/depression factor) (Figure 43) 4 weeks N=1, n=156; SMD=-0.23, 95%CI: -0.56, 0.1 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases

Table 4 Summary of evidence table for the comparison of TAAR1 agonists versus placebo for efficacy outcomes in Parkinson’s disease psychosis. There were data from a single study for ulotaront.

Summary of evidence table for the comparison of TAAR1 agonists versus placebo for dropouts and side-effects in adults with psychosis, other mental health conditions and healthy volunteers

Outcome Timepoint Summary of the association Bias due to study limitations Bias due to. Reporting bias Bias due to indirectness Bias due to other reasons
Dropouts due to any reason (Figure 10) 1 day N=2, n=93; 11.7% vs. 4.7%, OR=2.67, 95%CI: 0.48, 14.8 (one study reported 0 events in both arms) Low risk: All studies had overall low risk of bias Some concerns: 16.7% of eligible studies and 14.9% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns: No usable data from studies in schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Dropouts due to any reason (Figure 11) 4-6 weeks N=5, n=1396; Random-effects: 22.9% vs. 19.6%, OR=1.22, 95%CI: 0.93, 1.60; Fixed-effecs: OR=1.22, 95%CI: 0.93, 1.60 Low risk: All studies had overall low risk of bias Low risk: 83.3% of eligible studies and 90.1% of participants had usable data. Low risk: 80% studies and 97.2% participants with schizophrenia. Low risk: No indication of other biases
Dropouts due to adverse events (Figure 12) 1 day N=3 n=161; 0.5% vs. 1.6%, OR=0.33, 95%CI: 0.02, 5.72 Low risk: 66.7% had overall low risk of bias. Some concerns: 25% of eligible studies and 25.7% of participants had usable data. The impact of the bias on the magnitude and direction is unclear, yet the number of dropouts in single doses studies should be small. Some concerns: 33.3% studies and 42.2% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Dropouts due to adverse events (Figure 13) 4-6 weeks N=3 n=497; Random-effects: 8.1% vs. 7.1%, OR=1.15, 95%CI: 0.58, 2.29; Fixed-effecs: OR=1.19, 95%CI: 0.6, 2.34 Low risk: All studies had overall low risk of bias Some concerns: 50% of eligible studies and 32.1% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: 66.7% studies and 92.2% participants with schizophrenia. Low risk: No indication of other biases
Serious adverse events (Figure 14) 1 day to 2 weeks N=4 n=177; Random-effects: 4.6% vs. 1.6%, OR=3.02, 95%CI: 0.36, 25.76; Fixed-effecs: OR=3.02, 95%CI: 0.36, 25.76 Low risk: 75% had overall low risk of bias Some concerns: 33.3% of eligible studies and 28.3% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns: 25% studies and 38.4% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Serious adverse events (Figure 15) 4-6 weeks N=3 n=497; Random-effects: 2.7% vs. 2.7%, OR=0.97, 95%CI: 0.28, 3.38; Fixed-effecs: OR=1.01, 95%CI: 0.32, 3.21 Low risk: All studies had overall low risk of bias Some concerns: 50% of eligible studies and 32.1% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: 66.7% studies and 92.2% participants with schizophrenia Low risk: No indication of other biases
Mortality due to any cause 1 day to 2 weeks N=4 n=177; not estimable effect size 0 events in both arms Low risk: All studies had overall low risk of bias Some concerns: 33.3% of eligible studies and 28.3% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns: 25% studies and 38.4% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Mortality due to any cause (Figure 16) 4-6 weeks N=3 n=497; 3% vs. 1%, OR=3.15, 95%CI: 0.13, 78.11 Low risk: All studies had overall low risk of bias Some concerns: 50% of eligible studies and 32.1% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: 66.7% studies and 92.2% participants with schizophrenia Low risk: No indication of other biases
Any adverse event (Figure 17) 1 day to 2 weeks N=4 n=177; Random-effects: 52.3% vs. 11.4%, OR=8.49, 95%CI: 1.73, 41.66; Fixed-effecs: OR=9.3, 95%CI: 3.92, 22.08 Low risk: 75% had overall low risk of bias Some concerns: 33.3% of eligible studies and 28.3% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns. 25% studies and 38.4% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Any adverse event (Figure 18) 4-6 weeks N=3 n=497; Random-effects: 48.7% vs. 54.6%, OR=0.79, 95%CI: 0.54, 1.15; Fixed-effecs: OR=0.78, 95%CI: 0.54, 1.15 Low risk: All studies had overall low risk of bias Some concerns: 50% of eligible studies and 32.1% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: 66.7% studies and 92.2% participants with schizophrenia Low risk: No indication of other biases
Anticholinergic symptom (Figure 19) 1 day N=1 n=69; 15.3% vs. 1.4%, OR=12.44, 95%CI: 0.66, 234.38 Low risk: 1 study with an overall low risk of bias Some concerns: 8.3% of eligible studies and 11% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Hypotension (Figure 20) 6 weeks N=1 n=39; 52.4% vs. 78.6%, OR=0.3, 95%CI: 0.07, 1.32 Low risk: 1 study with an overall low risk of bias Some concerns: 16.7% of eligible studies and 2.5% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Dizziness (Figure 21) 1 day N=2 n=137; Random-effects: 19.9% vs. 3.5%, OR=6.89, 95%CI: 1.98, 23.92; Fixed-effecs: OR=6.89, 95%CI: 1.98, 23.92 Low risk: 50% had overall low risk of bias Some concerns: 16.7% of eligible studies and 21.9% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns: 50% studies and 49.6% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Dizziness (Figure 22) 6 weeks N=1 n=39; 16% vs. 7.1%, OR=2.48, 95%CI: 0.25, 24.65 Low risk: 1 study with an overall low risk of bias Some concerns: 16.7% of eligible studies and 2.5% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Nausea/vomitting (Figure 23) 1 day N=3 n=161; Random-effects: 19.5% vs. 1.6%, OR=15.14, 95%CI: 3.71, 61.75; Fixed-effecs: OR=15.14, 95%CI: 3.71, 61.75 Low risk: 66.7% had overall low risk of bias Some concerns: 25% of eligible studies and 25.7% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns: 33.3% studies and 42.2% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Nausea/vomitting (Figure 24) 4-6 weeks N=3 n=497; Random-effects: 3.9% vs. 4.4%, OR=0.88, 95%CI: 0.25, 3.15; Fixed-effecs: OR=0.92, 95%CI: 0.38, 2.24 Low risk: All studies had overall low risk of bias Some concerns: 50% of eligible studies and 32.1% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: 66.7% studies and 92.2% participants with schizophrenia Low risk: No indication of other biases
QTc prolongation (any cutoff) (Figure 25) 1 day N=2 n=92; 8.1% vs. 1.6%, OR=5.32, 95%CI: 0.6, 46.78 Low risk: 50% had overall low risk of bias Some concerns: 16.7% of eligible studies and 14.7% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: 50% studies and 73.9% participants with schizophrenia Low risk: No indication of other biases
QTc prolongation (any cutoff) 4 weeks N=1 n=245; not estimable effect size 0 events in both arms Low risk: 1 study with an overall low risk of bias Some concerns: 16.7% of eligible studies and 15.8% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: No clear indication of indirectness Low risk: No indication of other biases
QTc interval (msec) (Figure 26) 1 day N=1 n=62; MD=1.25, 95%CI: -2.87, 5.37 Low risk: 1 study with overall some concerns in risk of bias Some concerns: 8.3% of eligible studies and 9.9% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Weight increased (≥7% increase or any cutoff) (Figure 27) 4 weeks N=2 n=458; Random-effects: 1.1% vs. 1%, OR=1.04, 95%CI: 0.17, 6.47; Fixed-effecs: OR=1.04, 95%CI: 0.17, 6.47 Low risk: All studies had overall low risk of bias Some concerns: 33.3% of eligible studies and 29.5% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Weight (kg) (Figure 28) 4 weeks N=1 n=245; MD=0.4, 95%CI: -0.13, 0.93 Low risk: 1 study with an overall low risk of bias Some concerns: 16.7% of eligible studies and 15.8% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Prolactin elevation (any cutoff) 1 day N=1 n=24; not estimable effect size 0 events in both arms Low risk: 1 study with an overall low risk of bias Some concerns: 8.3% of eligible studies and 3.8% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Prolactin levels (ng/ml) (Figure 29) 4 weeks N=1 n=227; MD=-0.58, 95%CI: -7.87, 6.7 Low risk: 1 study with an overall low risk of bias Some concerns: 16.7% of eligible studies and 14.6% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Akathisia (Figure 30) 4 weeks N=1 n=245; 1.2% vs. 0.4%, OR=3.15, 95%CI: 0.13, 78.11 Low risk: 1 study with an overall low risk of bias Some concerns: 16.7% of eligible studies and 15.8% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Extrapyramidal symptoms (Figure 31) 4 weeks N=1 n=245; 3.3% vs. 3.2%, OR=1.04, 95%CI: 0.25, 4.27 Low risk: 1 study with an overall low risk of bias Some concerns: 16.7% of eligible studies and 15.8% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Anxiety 1 day N=1 n=69; not estimable effect size 0 events in both arms Low risk: 1 study with an overall low risk of bias Some concerns: 8.3% of eligible studies and 11% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Anxiety (Figure 32) 4 weeks N=2 n=458; Random-effects: 2.6% vs. 7.6%, OR=0.32, 95%CI: 0.12, 0.85; Fixed-effecs: OR=0.31, 95%CI: 0.12, 0.8 Low risk: All studies had overall low risk of bias Some concerns: 33.3% of eligible studies and 29.5% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Agitation (Figure 33) 4 weeks N=2 n=458; Random-effects: 5.5% vs. 4.2%, OR=1.35, 95%CI: 0.53, 3.43; Fixed-effecs: OR=1.38, 95%CI: 0.56, 3.45 Low risk: All studies had overall low risk of bias Some concerns: 33.3% of eligible studies and 29.5% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Headache (Figure 33) 1 day N=1 n=69; 11.5% vs. 20.6%, OR=0.5, 95%CI: 0.13, 1.89 Low risk: 1 study with an overall low risk of bias Some concerns: 8.3% of eligible studies and 11% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Headache (Figure 34) 4 weeks N=2 n=458; Random-effects: 7.9% vs. 9%, OR=0.86, 95%CI: 0.43, 1.69; Fixed-effecs: OR=0.86, 95%CI: 0.44, 1.68 Low risk: All studies had overall low risk of bias Some concerns: 33.3% of eligible studies and 29.5% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: No clear indication of indirectness Low risk: No indication of other biases
Sedation (Figure 36) 1 day N=3 n=161; Random-effects: 28.8% vs. 4.1%, OR=9.55, 95%CI: 3.5, 26.09; Fixed-effecs: OR=9.55, 95%CI: 3.5, 26.09 Low risk: 66.7% had overall low risk of bias Some concerns: 25% of eligible studies and 25.7% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: 33.3% studies and 42.2% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Sedation (Figure 37) 4-6 weeks N=2 n=284; Random-effects: 8.1% vs. 7.2%, OR=1.14, 95%CI: 0.44, 3; Fixed-effecs: OR=1.15, 95%CI: 0.44, 2.99 Low risk: All studies had overall low risk of bias Some concerns: 33.3% of eligible studies and 18.3% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: 50% studies and 86.3% participants with schizophrenia Low risk: No indication of other biases
Insomnia (Figure 38) 4 weeks N=3 n=497; Random-effects: 5.6% vs. 6%, OR=0.93, 95%CI: 0.17, 5.06; Fixed-effecs: OR=0.71, 95%CI: 0.32, 1.55 Low risk: All studies had overall low risk of bias Some concerns: 50% of eligible studies and 32.1% of participants had usable data. The impact of the bias on the magnitude and direction is unclear. Low risk: 66.7% studies and 92.2% participants with schizophrenia Low risk: No indication of other biases

Table 5 Summary of evidence table for the comparison of TAAR1 agonists versus placebo for dropouts and side-effects in adults with psychosis, other mental health conditions and healthy volunteers. There were data for ulotaront and ralmitaront.

Summary of evidence table for the comparison of TAAR1 agonists versus antipsychotics for dropouts and side-effects in adults with psychosis, other mental health conditions and healthy volunteers

Outcome Timepoint Summary of the association Bias due to study limitations Bias due to. Reporting bias Bias due to indirectness Bias due to other reasons
Dropouts due to any reason (Figure 46) 1 day N=1 n=71; 14.3% vs. 5.6%, OR=2.83, 95%CI: 0.51, 15.69 Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Dropouts due to any reason (Figure 47) 4 weeks N=1 n=214; 22.9% vs. 18.9%, OR=1.27, 95%CI: 0.63, 2.56 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Dropouts due to adverse events 1 day N=1 n=71; not estimable effect size 0 events in both arms Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Dropouts due to adverse events (Figure 48) 4 weeks N=1 n=214; 6.4% vs. 1.4%, OR=5.02, 95%CI: 0.62, 40.38 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Serious adverse events (Figure 49) 1 day N=1 n=71; 4.2% vs. 1.4%, OR=3.17, 95%CI: 0.13, 80.58 Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Serious adverse events (Figure 50) 4 weeks N=1 n=214; 2.5% vs. 0.7%, OR=3.79, 95%CI: 0.19, 74.42 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Mortality due to any cause 1 day N=1 n=71; not estimable effect size 0 events in both arms Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Mortality due to any cause 4 weeks N=1 n=214; not estimable effect size 0 events in both arms Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Any adverse event (Figure 51) 1 day N=1 n=71; 97.1% vs. 41.7%, OR=47.6, 95%CI: 5.85, 387.2 Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Any adverse event (Figure 52) 4 weeks N=1 n=214; 26.5% vs. 48.6%, OR=0.38, 95%CI: 0.21, 0.68 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Anticholinergic symptom (Figure 53) 1 day N=1 n=71; 15.3% vs. 1.4%, OR=13.16, 95%CI: 0.7, 247.71 Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Dizziness (Figure 54) 1 day N=1 n=71; 28.6% vs. 2.8%, OR=14, 95%CI: 1.68, 116.49 Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Nausea/vomitting (Figure 55) 1 day N=1 n=71; 34.7% vs. 1.4%, OR=38.83, 95%CI: 2.19, 687.51 Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Nausea/vomitting (Figure 56) 4 weeks N=1 n=214; 1.4% vs. 8.1%, OR=0.16, 95%CI: 0.03, 0.84 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Weight increased (any cutoff) (Figure 57) 4 weeks N=1 n=214; 1.4% vs. 10.8%, OR=0.12, 95%CI: 0.02, 0.58 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Anxiety (Figure 58) 1 day N=1 n=71; 1.2% vs. 8.3%, OR=0.13, 95%CI: 0.01, 2.71 Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Anxiety (Figure 59) 4 weeks N=1 n=214; 3.6% vs. 6.8%, OR=0.51, 95%CI: 0.14, 1.83 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Agitation (Figure 60) 4 weeks N=1 n=214; 6% vs. 0.7%, OR=9.56, 95%CI: 0.54, 167.96 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Headache (Figure 61) 1 day N=1 n=71; 11.4% vs. 2.8%, OR=4.52, 95%CI: 0.48, 42.59 Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Headache (Figure 62) 4 weeks N=1 n=214; 6.4% vs. 8.1%, OR=0.78, 95%CI: 0.27, 2.28 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases
Sedation (Figure 63) 1 day N=1 n=71; 60% vs. 13.9%, OR=9.3, 95%CI: 2.91, 29.72 Low risk: 1 study with an overall low risk of bias Low risk: 50% of eligible studies and 71% of participants had usable data Some concerns: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction is unclear. Low risk: No indication of other biases
Insomnia (Figure 64) 4 weeks N=1 n=214; 5.7% vs. 6.8%, OR=0.84, 95%CI: 0.26, 2.65 Low risk: 1 study with an overall low risk of bias Low risk: 1 eligible study with usable data Low risk: No clear indication of indirectness Low risk: No indication of other biases

Table 6 Summary of evidence table for the comparison of TAAR1 agonists versus placebo for dropouts and side-effects in adults with psychosis, other mental health conditions and healthy volunteers. There were data for ulotaront vs. amisulpride (single dose) and ralmitaront vs. risperidone (4 weeks).